Our laboratory is interested in the mechanisms through which receptor selective opioids influence the neuronal activity of "pain" transmission neurons in the spinal cord. To this end, we have been studying the expression of the fos protein product of the c-fos proto-oncogene as a marker of noxious stimulus-evoked neuronal activity in large populations of spinal cord neurons. since the behavior of the animals as well as the presence of fos-like immunoreactivity can be assessed in the same animal, we have been able to correlate the inhibition of pain behavior produced by opioids with changes in the distribution and numbers of fos- immunoreactive neurons. Those studies demonstrated that behavioral analgesia can be produced without completely eliminating the noxious stimulus-evoked expression of fos in the spinal cord and that dose dependent changes differed in different regions of the cord. In the proposed studies we first will extend this analysis to the effects produced by opioids acting at the mu, delta and kappa receptors, administered supraspinally and at the level of the cord. Second, we will begin an analysis of noxious stimulus-evoked fos expression in the opioid tolerant animal. We will test the hypothesis that the pattern and magnitude of fos expression in the spinal cord is altered from that in normal animals, even though pain behavior returns to "normal". Since opioid antagonists precipitate a hyperalgesic state when the spinal cord is made tolerant to opioids, in related studies, we will compare the pattern of pain-evoked fos expression in tolerant animals with that produced when abstinence-associated pain is precipitated. Finally, since our studies have identified a critical contribution of neurons in the ventral horn of the spinal cord (laminae VII and VIII) to the transmission of nociceptive messages, we will begin a detailed analysis of the synaptic circuitry that regulates neurons in these regions. Taken together these studies will reveal how populations of neurons are affected under conditions of pain, opioid analgesia, tolerance and abstinence. Understanding how different neuronal populations respond is an important step in developing pharmacological approaches to selective regulation of these neuronal populations, so that better pain control, with reduced tolerance and side effects, can be achieved.